Certain nitrogen containing bicyclic chemical entities for treating viral infections

Abstract

Provided are certain chemical entities, pharmaceutical compositions, and methods of treatment of a member of the flaviviradae family of viruses such as hepacivirus (Hepatitis C or HCV).

1 . At least one chemical entity selected from compounds of Formula 1: 
     
       
         
         
             
             
         
       
     
     and pharmaceutically acceptable salts thereof, wherein
 W 1  is selected from CR 1  and NR 1 ; 
 W 3  is selected from CR 3  and NR 3 ; 
 W 4  is selected from CR 4  and N; 
 W 6  is selected from CR 6  and N; 
 W 8  is selected from C and N; 
 W 9  is selected from C and N; 
 R 1  is absent or is selected from hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted amino, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, —OR 15 , —SR 15 , —S(O)R 16 , —S(O) 2 R 16 , —S(O) 2 NR 10 R 11 , —NR 10 R 11 , —NR 11 C(O)NR 10 R 11 , —NR 11 C(S)NR 10 R 11 , —NR 11 S(O) 2 R 14 —NR 11 C(O)OR 13 , —NR 11 C(O)R 12 , —C(NR 11 )NR 10 R 11 , —C(O)NR 10 R 11 , —C(O)OR 13 , —CN, —NO 2 , and —C(O)R 12 ; 
 R 2  is selected from halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted amino, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, —OR 15 , —SR 15 , —S(O)R 16 , —S(O) 2 R 16 , —S(O) 2 NR 10 R 11 , —NR 10 R 11 , —NR 11 C(O)NR 10 R 11 , —NR 11 C(S)NR 10 R 11 , —NR 11 S(O) 2 R 14 —NR 11 C(O)OR 13 , —NR 11 C(O)R 12 , —C(NR 11 )NR 10 R 11 , —C(O)NR 10 R 11 , —C(O)OR 13 , —CN, —NO 2 , and —C(O)R 12 ; 
 R 3  is absent or is selected from hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted amino, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, —OR 15 , —SR 15 , —S(O)R 16 , —S(O) 2 R 16 , —S(O) 2 NR 10 R 11 , —NR 10 R 11 , —NR 11 C(O)NR 10 R 11 , —NR 11 C(S)NR 10 R 11 , —NR 11 S(O) 2 R 14 —NR 11 C(O)OR 13 , —NR 11 C(O)R 12 , —C(NR 11 )NR 10 R 11 , —C(O)NR 10 R 11 , —C(O)OR 13 , —CN, —NO 2 , and —C(O)R 12 ; 
 R 4  is selected from hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted amino, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, —OR 15 , —SR 15 , —S(O)R 16 , —S(O) 2 R 16 , —S(O) 2 NR 10 R 11 , —NR 10 R 11 , —NR 11 C(O)NR 10 R 11 , —NR 11 C(S)NR 10 R 11 , —NR 11 S(O) 2 R 14 —NR 11 C(O)OR 13 , —NR 11 C(O)R 12 , —C(NR 11 )NR 10 R 11 , —C(O)NR 10 R 11 , —C(O)OR 13 , —CN, —NO 2 , and —C(O)R 12 ; 
 R 5  is selected from halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted amino, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, —OR 15 , —SR 15 , —S(O)R 16 , —S(O) 2 R 16 , —S(O) 2 NR 10 R 11 , —NR 10 R 11 , —NR 11 C(O)NR 10 R 11 , —NR 11 C(S)NR 10 R 11 , —NR 11 S(O) 2 R 14 —NR 11 C(O)OR 13 , —NR 11 C(O)R 12 , —C(NR 11 )NR 10 R 11 , —C(O)NR 10 R 11 , —C(O)OR 13 , —CN, —NO 2 , and —C(O)R 12 ; 
 R 6  is selected from hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted amino, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, —OR 15 , —SR 15 , —S(O)R 16 , —S(O) 2 R 16 , —S(O) 2 NR 10 R 11 , —NR 10 R 11 , —NR 11 C(O)NR 10 R 11 , —NR 11 C(S)NR 10 R 11 , —NR 11 S(O) 2 R 14 —NR 11 C(O)OR 13 , —NR 11 C(O)R 12 , —C(NR 11 )NR 10 R 11 , —C(O)NR 10 R 11 , —C(O)OR 11 , —CN, —NO 2 , and —C(O)R 12 ; 
 R 7  is selected from halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted amino, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, —OR 15 , —SR 15 , —S(O)R 16 , —S(O) 2 R 16 , —S(O) 2 NR 10 R 11 , —NR 10 R 11 , —NR 11 C(O)NR 10 R 11 , —NR 11 C(S)NR 10 R 11 , —NR 11 S(O) 2 R 14 —NR 11 C(O)OR 13 , —NR 11 C(O)R 12 , —C(NR 11 )NR 10 R 11 , —C(O)NR 10 R 11 , —C(O)OR 11 , —CN, —NO 2 , and —C(O)R 12 ; 
 R 10  and R 11  are independently selected from hydrogen, optionally substituted alkyl, optionally substituted amino, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl, or R 10  and R 11 , taken together with any intervening atoms, form a ring system selected from optionally substituted heterocycloalkyl, and optionally substituted heteroaryl; 
 R 12  is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; 
 R 13  is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; 
 R 14  is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; 
 R 15  is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; and 
 R 16  is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; 
 provided that
 if W 1  is NR 1  and W 3  is NR 3 , then R 3  is absent; 
 if W 3  is NR 3  and W 1  is NR 1 , then R 1  is absent; 
 at least one of W 1 , W 3 , W 8 , and W 9  is N; 
 no more than four of W 1 , W 3 , W 4 , W 6 , W 8 , and W 9  are N; and 
 if W 1  is N, W 4  is N, and W 6  is CR 16 , then W 8  is not N; 
 
 and further provided that the compound of Formula 1 is not 
 
     (5-(5-chlorothiophen-2-yl)-7-(trifluoromethyl)pyrazolo[1,5-a]pyridin-2-yl)(3-(3,4-dimethoxyphenyl)-5-(2-hydroxyphenyl)-4,5-dihydro-1H-pyrazol-1-yl)methanone; 
     (5-(5-chlorothiophen-2-yl)-7-(trifluoromethyl)pyrazolo[1,5-a]pyridin-2-yl)(3-(2,5-dimethylphenyl)-5-(2-hydroxyphenyl)-4,5-dihydro-1H-pyrazol-1-yl)methanone; or 
     (5-(5-chlorothiophen-2-yl)-7-(trifluoromethyl)pyrazolo[1,5-a]pyridin-2-yl)(3-(3,4-dichlorophenyl)-5-(2-hydroxyphenyl)-4,5-dihydro-1H-pyrazol-1-yl)methanone. 
   
   
       2 . At least one chemical entity of  claim 1  wherein R 5  is selected from optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocycloalkyl. 
   
   
       3 . At least one chemical entity of  claim 1  wherein the compound of Formula 1 is selected from the following compounds: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
   
   
       4 . At least one chemical entity of  claim 3  wherein R 5  is selected from optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocycloalkyl. 
   
   
       5 . At least one chemical entity of  claim 1  wherein the compound of Formula 1 is selected from the following compounds: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
   
   
       6 . At least one chemical entity of  claim 5  wherein R 5  is selected from optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocycloalkyl. 
   
   
       7 . At least one chemical entity of  claim 1  wherein the compound of Formula 1 is selected from the following compounds: 
     
       
         
         
             
             
         
       
     
   
   
       8 . At least one chemical entity of  claim 7  wherein R 5  is selected from optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocycloalkyl. 
   
   
       9 . At least one chemical entity of  claim 1  wherein the compound of Formula 1 is selected from the following compounds: 
     
       
         
         
             
             
         
       
     
   
   
       10 . At least one chemical entity of  claim 9  wherein the compound of Formula 1 is selected from the following compounds: 
     
       
         
         
             
             
         
       
     
   
   
       11 . At least one chemical entity of  claim 10  wherein the compound of Formula 1 is 
     
       
         
         
             
             
         
       
     
   
   
       12 . At least one chemical entity of  claim 9  wherein R 5  is selected from optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocycloalkyl. 
   
   
       13 . At least one chemical entity of  claim 1  wherein R 2  is selected from optionally substituted alkyl, —NR 11 S(O) 2 R 14 , —NR 11 C(O)NR 10 R 11 , —NR 11 C(O)OR 13 —C(O)NR 10 R 11 , and —C(O)OR 13 . 
   
   
       14 . At least one chemical entity of  claim 13  wherein R 2  is lower alkyl substituted with —NR 10 R 11 . 
   
   
       15 - 18 . (canceled) 
   
   
       19 . At least one chemical entity of  claim 14  wherein R 10  and R 11 , together with any intervening atoms, form a substituted 3- to 7-membered nitrogen containing heterocycloalkyl which optionally further includes one or two additional heteroatoms chosen from N, O, S, S(O), S(O) 2 , and P(O), wherein said 3- to 7-membered nitrogen containing heterocycloalkyl is substituted with a group —Y—R 30  and optionally substituted with a second group R 31 , wherein
 Y is a bond or is selected from —NR 10 —, —NR 11 SO 2 —, —O—, —S—, —C(O)NR 10 —, and —S(O) 2 R 10 —;   R 30  is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; and   R 31  is selected from halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxy, —OH, —SH, —NO 2 , —NR 10 R 11 , —C(O)NR 10 R 11 , —C(O)OR 13 , —SO 2 NR 10 R 11 , —NR 11 C(S)NR 10 R 11 , —NR 11 C(O)NR 10 R 11 , —CN, —NR 11 SO 2 R 14 , and —NR 11 CO 2 R 13 .   
   
   
       20 . At least one chemical entity of  claim 19  wherein R 10  and R 11 , together with any intervening atoms, form a substituted 3- to 7-membered nitrogen containing heterocycloalkyl which optionally further includes one or two additional heteroatoms chosen from N, O, S, S(O), S(O) 2 , and P(O), wherein said 3- to 7-membered nitrogen containing heterocycloalkyl is substituted with a group —Y—R 30  and optionally substituted with a second group R 31 , wherein
 Y is a bond or is selected from —O—, —S—, —C(O)NR 10 —, and —S(O) 2 R 10 —;   R 30  is selected from optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; and   R 31  is selected from halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxy, —NO 2 , —NR 10 R 11 , —C(O)NR 10 R 11 , —C(O)OR 13 , —SO 2 NR 10 R 11 , —NR 11 C(S)NR 10 R 11 , —NR 11 C(O)NR 10 R 11 , —CN, —NR 11 SO 2 R 14 , and —NR 11 CO 2 R 13 .   
   
   
       21 - 68 . (canceled) 
   
   
       69 . At least one chemical entity of  claim 1  wherein the compound of Formula 1 is chosen from compounds of Table 1, Table 2, and Table 3. 
   
   
       70 . A pharmaceutical composition comprising a pharmaceutically acceptable diluent and a therapeutically effective amount of at least one chemical entity of  claim 1 . 
   
   
       71 . A pharmaceutical composition comprising a pharmaceutically acceptable diluent and a therapeutically effective amount of at least one chemical entity chosen from compounds of Formula 1a 
     
       
         
         
             
             
         
       
     
     and pharmaceutically acceptable salts thereof, wherein
 W 3  is selected from CR 3  and NR 3 ; 
 R 2  is selected from halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted amino, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, —OR 15 , —SR 15 , —S(O)R 16 , —S(O) 2 R 16 , —S(O) 2 NR 10 R 11 , —NR 10 R 11 , —NR 11 C(O)NR 10 R 11 , —NR 11 C(S)NR 10 R 11 , —NR 11 S(O) 2 R 14 —NR 11 C(O)OR 13 , —NR 11 C(O)R 12 , —C(NR 11 )NR 10 R 11 , —C(O)NR 10 R 11 , —C(O)OR 13 , —CN, —NO 2 , and —C(O)R 12 ; 
 R 3  is absent or is selected from halogen, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted amino, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, —OR 15 , —SR 15 , —S(O)R 16 , —S(O) 2 R 16 , —S(O) 2 NR 10 R 11 , —NR 10 R 11 , —NR 11 C(O)NR 10 R 11 , —NR 11 C(S)NR 10 R 11 , —NR 11 S(O) 2 R 14 —NR 11 C(O)OR 13 , —NR 11 C(O)R 12 , —C(R 11 )NR 10 R 11 , —C(O)NR 10 R 11 , —C(O)OR 13 , —CN, —NO 2 , and —C(O)R 12 ; 
 R 5  is selected from halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted amino, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, —OR 15 , —SR 15 , —S(O)R 16 , —S(O) 2 R 16 , —S(O) 2 NR 10 R 11 , —NR 10 R 11 , —NR 11 C(O)NR 10 R 11 , —NR 11 C(S)NR 10 R 11 , —NR 11 S(O) 2 R 14 —NR 11 C(O)OR 13 , —NR 11 C(O)R 12 , —C(R 11 )NR 10 R 11 , —C(O)NR 10 R 11 , —C(O)OR 13 , —CN, —NO 2 , and —C(O)R 12 ; 
 R 16  is selected from hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted amino, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, —OR 15 , —SR 15 , —S(O)R 16 , —S(O) 2 R 16 , —S(O) 2 NR 10 R 11 , —NR 10 R 11 , —NR 11 C(O)NR 10 R 11 , —NR 11 C(S)NR 10 R 11 , —NR 11 S(O) 2 R 14 —NR 11 C(O)OR 13 , —NR 11 C(O)R 12 , —C(R 11 )NR 10 R 11 , —C(O)NR 10 R 11 , —C(O)OR 11 , —CN, —NO 2 , and —C(O)R 12 ; 
 R 7  is selected from halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted amino, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, —OR 15 , —SR 15 , —S(O)R 16 , —S(O) 2 R 16 , —S(O) 2 NR 10 R 11 , —NR 10 R 11 , —NR 11 C(O)NR 10 R 11 , —NR 11 C(S)NR 10 R 11 , —NR 11 S(O) 2 R 14 —NR 11 C(O)OR 13 , —NR 11 C(O)R 12 , —C(NR 11 )NR 10 R 11 , —C(O)NR 10 R 11 , —C(O)OR 11 , —CN, —NO 2 , and —C(O)R 12 ; 
 R 10  and R 11  are independently selected from hydrogen, optionally substituted alkyl, optionally substituted amino, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl, or R 10  and R 11 , taken together with any intervening atoms, form a ring system selected from optionally substituted heterocycloalkyl, and optionally substituted heteroaryl; 
 R 12  is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; 
 R 13  is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; 
 R 14  is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; 
 R 15  is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; and 
 R 16  is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl. 
 
   
   
       72 - 116 . (canceled) 
   
   
       117 . A method for treating a viral infection in a mammal mediated at least in part by a virus in the flaviviridae family of viruses which method comprises administering to a mammal, that has been diagnosed with said viral infection or is at risk of developing said viral infection, a pharmaceutical composition according to  claim 70 , provided that at least one of R 1  and R 3  is halogen. 
   
   
       118 - 121 . (canceled)